Phosphodiesterase 4 inhibitors (PDE4 inhibitors) may be useful in the treatment and/or prophylaxis of a variety of diseases/conditions, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: chronic obstructive pulmonary disease (COPD) (e.g. chronic bronchitis and/or emphysema), asthma, rhinitis (e.g. allergic or non-allergic rhinitis), rheumatoid arthritis, atopic dermatitis, psoriasis, urticaria, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, septic shock, inflammatory bowel disease (e.g. ulcerative colitis and/or Crohn's disease), reperfusion injury of the myocardium and/or brain, chronic glomerulonephritis, endotoxic shock, or adult respiratory distress syndrome, in mammals such as humans.
Chronic obstructive pulmonary disease (COPD) is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (e.g., see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
PDE4 inhibitors, for example cilomilast and roflumilast, are thought to be effective in the treatment of COPD. For example, see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J. Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; A. M. Vignola, Respiratory Medicine, 2004, 98, 495-503; D. Spina, Drugs, 2003, 63(23), 2575-2594; and references cited in the aforementioned publications; G. Krishna et al., Expert Opinion on Investigational Drugs, 2004, 13(3), 255-267 (see especially pp. 259-261 and refs. 102-111 and 201 therein); and B. J. Lipworth, The Lancet, 2005, 365, 167-175.
The PDE4 inhibitor cilomilast (Ariflo™) at 15 mg orally twice daily appears to improve forced expiratory volume in 1s (FEV1) in COPD patients (C. H. Compton et al., The Lancet, 2001, vol. 358, 265-270), and appears to have antiinflammatory effects in COPD patients (E. Gamble et al., Am. J. Respir. Crit. Care Med., 2003, 168, 976-982). On cilomilast, see also R. D. Border et al., Chest, 2003, vol. 124 Suppl. 4, p. 170S (abstract) and J. D. Eddleston et al., Am. J. Respir. Crit. Care Med., 2001, 163, A277 (abstract). The PDE4 inhibitor roflumilast appears to show small improvements in FEV1 in COPD patients (see B. J. Lipworth, The Lancet, 2005, 365, 167-175, and refs 49-50 therein).
PDE4 inhibitors are thought to be effective in the treatment and/or prophylaxis of asthma (e.g. see M. A. Giembycz, Drugs, February 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5: 432-438; H. J. Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; P. J. Barnes, Nature Reviews—Drug Discovery, October 2004, 831-844; B. J. Lipworth, The Lancet, 2005, 365, 167-175; and references cited in the aforementioned publications).
The PDE4 inhibitor roflumilast, given orally at 500 ug once daily for 9 days, is reported to be effective in improving rhinal airflow during the treatment period (compared to placebo), in humans with histories of allergic rhinitis but asymptomatic at screening, and who were challenged with intranasal allergen provocation (pollen extracts) daily beginning the third day of treatment and each time approx. 2 hours after study drug administration (B. M. Schmidt et al., J. Allergy & Clinical Immunology, 108(4), 2001, 530-536).
PDE4 inhibitors may be effective in the treatment of rheumatoid arthritis (e.g. see H. J. Dyke et al., Expert Opinion on Investigational Drugs, January 2002, 11(1), 1-13; C. Burnouf et al., Current Pharmaceutical Design, 2002, 8(14), 1255-1296; and A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473; and references cited in these publications).
PDE4 inhibition has been suggested for the treatment of inflammatory bowel disease (e.g. ulcerative colitis and/or Crohn's disease), see K. H. Banner and M. A. Trevethick, Trends Pharmacol. Sci., August 2004, 25(8), 430-436.
For the use of PDE4 inhibitors in atopic dermatitis, see for example:                J. M. Hanifin et al., “Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis”, J. Invest. Dermatol., 1996, 107(1), 51-56; which reports reductions of inflammatory parameters in atopic dermatitis patients treated with PDE4 inhibitor CP80,633 (0.5% ointment, twice daily topical application);            C. E. M. Griffiths et al., “Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis”, Br. J. Dermatol., 2002, 147(2), 299-307, which reports that cipamfylline (0.15%) cream is significantly more effective than vehicle, but significantly less effective than hydrocortisone 17-butyrate (0.1%) cream, in the treatment of atopic dermatitis patients;            T. C. Roos et al., “Recent advances in treatment strategies for atopic dermatitis”, Drugs, 2004, 64(23), 2639-2666 (see e.g. page 2657 and refs. 201-209 therein);        A. M. Doherty, Current Opinion Chem. Biol., 1999, 3(4), 466-473 (e.g. see p. 470); and        H. J. Dyke et al., Expert Opinion Invest. Drugs, 2002, 11(1), 1-13 (e.g. see p. 7 and refs. 74, 75 and 76 cited therein);and references cited in the above references.        
For the use of the PDE4 inhibitors SB 207499 (cilomilast) and AWD 12-281 in mouse models of the allergic type of dermatitis, see W. Bäumer et al., Eur. J. Pharmacol., 2002, 446, 195-200 and W. Bäumer et al., J. Pharmacy Pharmacol., 2003, 55, 1107-1114.
WO 2004/056823 A1 (PCT/EP2003/014867, Glaxo Group Limited) discloses certain pyrazolo[3,4-b]pyridine compounds or salts thereof; and their use as PDE4 inhibitors.
WO 2004/024728 A2 (PCT/EP2003/011814, Glaxo Group Limited) discloses pyrazolo[3,4-b]pyridine compounds or salts thereof with a 4-NHR3 group and a 5-C(O)—X group, according to the following formula, wherein X is NR4R5 or OR5a, and R2 is a hydrogen atom (H), methyl or C1fluoroalkyl. These pyrazolo[3,4-b]pyridine compounds and salts are disclosed as being inhibitors of phosphodiesterase type IV (PDE4):

WO 2004/024728 has been reviewed, and WO 2004/056823 mentioned, in Expert Opin. Ther. Patents, 2005 (January edition), 15(1), 111-114.
Further pyrazolo[3,4-b]pyridine compounds or salts thereof, and their use as PDE4 inhibitors, are disclosed in patent publications WO 2005/058892 A1 (PCT/EP2004/014490), WO 2005/090348 A1 (PCT/GB2005/000983), WO 2005/090352 A1 (PCT/EP2005/003038), WO 2005/090353 A1 (PCT/GB2005/000976), WO 2005/090354 A1 (PCT/GB2005/000987) (all Glaxo Group Limited). Of these, WO 2005/090348 A1 discloses pyrazolo[3,4-b]pyridine compounds or salts thereof with a 4-NHR3 group and a 5-C(O)—NH—W group, according to the following formula, wherein W is Ar, —CR4R5Ar or a group (y) or (y1), and R2 is C2-6alkyl, C3-6cycloalkyl or —(CH2)n4C3-6cycloalkyl:

Copending patent application PCT/GB2006/003626, published on 5 Apr. 2007 as WO 2007/036733 A1, discloses pyrazolo[3,4-b]pyridine compounds of the following formula or salts thereof, and their use as PDE4 inhibitors:

Copending patent application PCT/GB2006/003627, published on 5 Apr. 2007 as WO 2007/036734 A1, discloses N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-3-methyl-5-isoxazolecarboxamide or a salt thereof, and its use as PDE4 inhibitor.